Submissions for variant NM_001145165.2(DOHH):c.455C>T (p.Pro152Leu)

gnomAD frequency: 0.00044  dbSNP: rs553950608

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002286537	SCV004013751	likely pathogenic	Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Missense changes are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 35858628). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.35; 3Cnet: 0.02). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DOHH -related disorder (ClinVar ID: VCV001285604). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 35858628). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587195	SCV005076624	uncertain significance	not specified	2024-04-23	criteria provided, single submitter	clinical testing	Variant summary: DOHH c.455C>T (p.Pro152Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 122338 control chromosomes (gnomAD). c.455C>T has been reported in the literature in the compound heterozygous state in an individual affected with Neurodevelopmental Disorder with cortical atrophy, ventricular dilatation, thin corpus callosum, and visual impairment (Ziegler_2022). These data do not allow any conclusion about variant significance. This publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in DOHH activity similar to the wild type. However, the authors suggest the variant may result in reduced stability, and the amount of DOHH protein in the patient's fibroblasts was reduced. The following publication has been ascertained in the context of this evaluation (PMID: 35858628). ClinVar contains an entry for this variant (Variation ID: 1285604). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Genetics, CHU d'Angers	RCV001868403	SCV001934585	pathogenic	DOHH related neurodevelopmental disorder	2021-09-22	no assertion criteria provided	research
OMIM	RCV002286537	SCV002576518	pathogenic	Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment	2022-09-30	no assertion criteria provided	literature only
Undiagnosed Diseases Network, NIH	RCV003163798	SCV003915637	likely pathogenic	DOHH-related disorder	2022-11-15	no assertion criteria provided	clinical testing